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Clinical Immunology & SerologyA Laboratory Perspective, Third Edition

Copyright © 2010 F.A. Davis CompanyCopyright © 2010 F.A. Davis Company

The Lymphoid System

Chapter Two


Copyright © 2010 F.A. Davis Company

The Lymphoid System

Lymphocytes represent between 20 and 40 percent of the circulating white blood cells.

The typical small lymphocyte is between 7 and 10 μm in diameter with a rounded nucleus that may be somewhat indented.

The nuclear chromatin is dense and tends to stain purple.



The Lymphoid System The lymphocyte’s cytoplasm is sparse,

contains few organelles with no specific granules, and stains a lighter blue.

Lymphocytes rise from a hematopoietic stem cell in the bone marrow and then are further differentiated in the primary lymphoid organs.

The primary lymphoid organs in humans are the bone marrow and the thymus.



The Lymphoid System The secondary organs in the lymphoid

system include the spleen, lymph nodes, appendix, tonsils, and other mucosal-associated lymphoid tissue (MALT).

It is in the secondary organs that the main contact with foreign antigens takes place.

The spleen serves as a filtering mechanism for removing antigens from the bloodstream.



The Lymphoid System The lymph nodes filter interstitial fluid from

the tissues. Mucosal surfaces in the respiratory and

alimentary tracts are backed with lymphoid tissue as an additional means of contacting foreign antigens as they enter the body.

Circulation of the lymphatic fluid is complex and promoted by skeletal and smooth muscle contractions.



The Lymphoid System T lymphocytes are effector cells that serve a

regulatory role. B lymphocytes produce antibodies. Both T and B lymphocytes recirculate

continuously from the bloodstream to the secondary lymphoid organs and back, to increase contact with foreign antigens.



The Lymphoid System A third type of lymphocyte, the NK cell, is

large, somewhat granular, and plays a role as a surveillance cell in both the innate and adaptive immune response.



The Lymphoid System T, B, and NK cells arise from a

common precursor known as the common lymphoid precursor (CLP) (see Fig. 2-2).

Lymphocyte precursors: lymphoblast, prolymphocyte

The bone marrow functions as the center for antigen-independent lymphopoiesis.



The Lymphoid System Following release from the marrow,

lymphocyte precursors are further developed in the primary lymphoid organs.

One subset goes to the thymus and develops into T cells.

B-cell maturation takes place within the bone marrow itself.



The Lymphoid System In the peripheral blood, approximately 10–20

percent of all lymphocytes are B cells, 61–89 percent are T cells, and up to 22 percent are NK cells.20%



The Lymphoid System T cells develop their

identifying characteristics in the thymus (see Fig. 2-3).

Surface markers (CD markers) are acquired as the lymphocytes travel from the cortex to the medulla in the thymus over a period of 2–3 weeks.

Mature T lymphocytes are then released from the medulla.



The Lymphoid System Once differentiation occurs, mature T and B

lymphocytes are released from the bone marrow and the thymus. They migrate to secondary lymphoid organs and become part of a recirculating pool.



The Lymphoid System The secondary lymphoid

organs include the spleen, lymph nodes, tonsils, appendix, Peyer’s patches in the intestines, and other mucosal-associated lymphoid tissue (MALT; see Fig. 2-3).

Lymphocytes in these organs travel through the tissue via the lymphatic vessels and return to the bloodstream by way of the thoracic duct.



The Lymphoid System When lymphopoiesis, or reproduction of

lymphocytes, occurs in the secondary tissue, it is strictly dependent on antigenic stimulation.specifically by MHC

Formation of lymphocytes in the bone marrow is antigen independent.



The Lymphoid System Most naïve or resting lymphocytes die within a

few days after leaving the primary lymphoid organs unless activated by the presence of a foreign antigen.

Lymphopoiesis following antigenic stimulation gives rise to long-lived memory cells and shorter-lived effector cells that are responsible for the generation of the immune response.plasma cell



The Lymphoid System The spleen is the largest secondary lymphoid

organ. The red pulp makes up more than one-half of the total splenic volume; its function is to

destroy old red blood cells and constantly search for infectious agents or other foreign matter.



The Lymphoid System Lymph nodes are located along lymphatic

vessels and serve as central collecting points for lymph fluid from adjacent tissues.

Lymph fluid arises from passage of fluids and low-molecular-weight solutes out of blood vessel walls and into the interstitial spaces.

Lymph nodes are especially numerous near joints and where the arms and legs join the body (axillary and inguinal nodes)



The Lymphoid System Filtration is a main

function of the lymph nodes.

The lymph nodes contain sinuses, which are lined with macrophages, creating an ideal location for phagocytosis to take place.

The tissue is organized into an outer cortex, a paracortex, and an inner medulla (see Fig. 2-5).



The Lymphoid System The outermost layer, the cortex, contains

macrophages and aggregations of B cells in primary follicles similar to those found in the spleen.

These B lymphocytes are mature, resting B cells that have not yet been exposed to antigen.



The Lymphoid System Secondary follicles consist of antigen-

stimulated proliferating B cells. The interior of a secondary follicle is known as

the germinal center, where blast transformation of B cells takes place.

Blastogenesis is triggered by IL-2, secreted by T helper cells.



The Lymphoid System Plasma cells, which actively secrete

antibody, and B memory cells, carrying membrane-bound antibody, are present in the germinal center.



The Lymphoid System Particulate antigens are removed by

macrophages, processed, and presented to the lymphocytes as the fluid travels across the lymph node from cortex to medulla.

Fluid and lymphocytes exit by way of the efferent lymph vessels.

These eventually connect with the thoracic duct and the venous system.



The Lymphoid System Additional areas of lymphoid tissue include

the MALT, tonsils, appendix, and cutaneous-associated lymphoid tissue.

MALT(mucosal-associated lymphoid tissue) is found in the gastrointestinal, respiratory, and urogenital tracts.

Peyer’s patches represent a specialized type of MALT and are located at the lower ileum of the intestinal tract.



The Lymphoid System The tonsils are another area of lymphoid

tissue found in the mucous membrane lining of the oral and pharyngeal cavities.

An additional location of lymphoid tissue is the appendix at the juncture of the small and large intestines.



The Lymphoid System Within each of these secondary organs, T and

B cells are segregated. B cells differentiate into memory cells and

plasma cells and are responsible for humoral immunity or antibody formation.

T cells play a role in cell-mediated immunity and produce sensitized lymphocytes that secrete cytokines.



The Lymphoid System B cells are derived from a multipotential

progenitor cell (stem cell) , a lymphoid-myeloid precursor that differentiates to become either a common myeloid progenitor or an early lymphocyte progenitor.



The Lymphoid System Early lymphocyte progenitors become T-cell,

B-cell, NK-cell, or dendritic cell precursors depending on exposure to different cytokines (see Fig. 2-6).



The Lymphoid System The earliest B-cell precursor can be

recognized by the presence of a surface molecule called CD45R (common to all wbcs).

B-cell precursors go through a developmental process that prepares them for their role in antibody production and restricts the types of antigens to which the cell can respond.

This part of B-cell development is known as the antigen-independent phase.



The Lymphoid System Under the influence of growth factors and

cytokines, rearrangement of genes occurs that will code for the heavy and light chains of an antibody molecule.

At this stage the cell is called a pro-B cell.



The Lymphoid System The pro-B cell has distinctive markers that

include surface antigens CD19, CD45R, CD43, CD24, and c-Kit. Intracellular proteins at this stage include TdT, necessary for gene rearrangement (marker of immature cells).

Differentiation of pro-B cells into pre-B cells occurs upon successful rearrangement of heavy-chain genes.



The Lymphoid System When synthesis of the heavy chain part of the

antibody molecule occurs, the pre-B stage begins.

Pre-B cells lose the CD43 marker as well as c-Kit and TdT.

Mu (μ) chains accumulate in the cytoplasm.



The Lymphoid System It appears that only pre-B cells expressing the

μ heavy chains in association with surrogate light chains survive and proceed to further differentiation.

Although these cells have complete IgM molecules on the cell surface, they are still immature.



The Lymphoid System Other surface proteins that appear on the

immature B cell include CD21, CD40, and major histocompatibility complex (MHC) class II molecules.



The Lymphoid System CD21 acts a receptor for a breakdown product

of the complement component C3, known as C3d.

This enhances the likelihood of contact between B cells and antigen, because antigen frequently becomes coated with complement fragments during the immune response.



The Lymphoid System CD40 and MHC class II are important for

interaction of B cells with T cells. Self-reactive B cells are deleted from the

marrow by the process of programmed cell death, or apoptosis.

Immature B cells leave the bone marrow and proceed to seed the spleen and other secondary lymphoid organs.



The Lymphoid System In the spleen, immature B cells develop into mature B-

cells These B cells remain in the spleen to respond quickly to

any bloodborne pathogens they may come into contact with.

Other immature B cells become follicular B cells, which are found in lymph nodes and other secondary organs.

The end result is a B lymphocyte programmed to produce a unique antibody molecule, consisting of two identical light chains and two identical heavy chains.



The Lymphoid System In addition to IgM, all

mature B cells exhibit IgD, another class of antibody molecule, on their surface (see Fig. 2-6D).IgD may prolong the life span of mature B cells in the periphery, and regulates isotype switching.

Unless contact with antigen occurs, the life span of a mature B cell is typically only a few days.



The Lymphoid System If a B cell is stimulated by antigen, it

undergoes transformation to a blast stage, which eventually forms memory cells and antibody-secreting plasma cells.

This process is known as the antigen-dependent phase of B-cell development.

These B cells have a half-life of more than 6 weeks.



The Lymphoid System Antigen-dependent activation of B cells takes

place in the primary follicles of peripheral lymphoid tissue.

Activated B cells exhibit identifying markers, including CD25, which is found on both activated T and B cells and acts as a receptor for interleukin- 2 (IL-2), a growth factor produced by T cells.



The Lymphoid System Plasma cells are

spherical or ellipsoidal cells between 10 and 20 μm in size with an eccentric nucleus and abundant deep blue cytoplasm containing immunoglobulin and little to no surface immunoglobulin (see Fig. 2-8).



The Lymphoid System Plasma cells are not normally found in the

blood but are located in germinal centers in the peripheral lymphoid organs.

Plasma cells are nondividing, and after several days of antibody production, they die without further proliferation.



The Lymphoid System Memory cells (see Fig.

2-7) are also found in germinal centers and have a much longer life span than a resting B cell.

They remain in an activated state for months or years, ready to respond again to the initial antigen.



The Lymphoid SystemT-Cell Differentiation 60 to 80 percent of circulating lymphocytes in

the peripheral blood are T cells, and these become differentiated in the thymus.

Lymphocyte precursors called thymocytes enter the thymus from the bone marrow.



The Lymphoid System This process is driven by chemokines.. There is an orderly rearrangement of the

genes coding for the antigen receptor (TCR). At the same time, distinct surface markers

appear during specific stages of development.



The Lymphoid System Two chains of the TCR, the

alpha (α) and beta (β) chains, contain variable regions that recognize specific antigens (see Fig. 2-10)

The remaining four chains comprise a complex called CD3 which is involved in signal transduction.



The Lymphoid System The appearance of a functional β chain on the

cell surface sends a signal to suppress any further β chain gene rearrangements.

Signaling by the β chain also triggers the thymocyte to become CD4-positive (CD4+) and CD8-positive (CD8+).



The Lymphoid System At this second stage, when thymocytes

express both CD4 and CD8 antigens, they are called double-positive cells.

Double-positive thymocytes proliferate and then begin to rearrange the genes coding for the alpha chain.

Only double-positive T cells with functional TCR complexes will survive this positive selection process.



The Lymphoid System Any thymocytes that are unable to recognize

self-MHC antigens die without leaving the thymus.

This negative selection process takes place among the surviving double-positive T cells.

Strong reactions with self-peptides send a signal to delete the developing T cell by means of apoptosis.



The Lymphoid System Survivors of selection exhibit only one type of

marker, either CD4 or CD8, and they migrate to the medulla of the thymus.

CD4+ cells, termed T-helper or inducer cells, represent ~ 2/3 of peripheral T cells. They recognize antigen bound to MHC class II protein.CD 8+ cells, termed T-cytotoxic cells, represent ~ 1/3 of peripheral T cells. They recognize antigen linked to MHC class I proteins.



The Lymphoid System These mature T cells are released from the

thymus and seed peripheral lymphoid organs. Resting T cells have a life span of up to

several years in these peripheral organs. Th1 cells produce interferon gamma (IFN-γ)

and tumor necrosis factor-beta (TNF-β), which protect cells against intracellular pathogens.



The Lymphoid System Th2 cells produce a variety of interleukins,

including IL-4, IL-5,IL-10, and IL-13. The essential role of the Th2 cells is to help B

cells produce antibody against extracellular pathogens.

A third class of T cells, regulatory cells (T reg), possess CD4 antigen and CD25 antigens.

Treg cells produce IL-10 which switches off the immune response (down-regulates genes)



The Lymphoid System T regulatory cells prevent autoimmune

reactions in any surviving T cells that can react with self-antigens.



The Lymphoid System Antigen activation occurs next. Antigen must be transported to the T-cell

zones of the secondary lymphoid tissue. When antigen recognition occurs, the

activated lymphocytes are transformed into lymphoblasts.

Activated T lymphocytes express receptors for IL-2 (CD 25), as activated B cells do.



The Lymphoid System T lymphoblasts differentiate into functionally

active small lymphocytes that produce cytokines.

Activities of specific cytokines include assisting B cells, killing target cells, promoting blast cell division, etc.

In addition to effector cells, T memory cells are also generated. They are able to proliferate faster than naïve T cells.



The Lymphoid System T memory cells also express a broader array

of cytokines and appear to persist for years. All the activities of T cells constitute cell-

mediated immunity. Table 2-2 summarizes the differences

between T cells and B cells in structure and function.



The Lymphoid System Natural killer cells are a small percentage of

lymphocytes that do not express the markers of either T cells or B cells (double neg. cells). Cell markers are CD 16, which acts as a receptor for the Fc end of Ig, and CD 56.

These large, granular lymphocytes make up 5 to 10 percent of the circulating lymphoid pool found mainly in the spleen and peripheral blood.



The Lymphoid System NK cells lack specificity in their response; this is

essential to their function as early defenders against viral pathogens and tumor cells. They have the ability to mediate cytolytic reactions (TNF) and kill target cells without prior exposure to them. They do not require MHC-processed antigen. Part of "natural immunity".

This gives time for the acquired response of specific T and B cells to be activated.



The Lymphoid System NK cells arise from the common lymphocyte

precursor (CLP) and differentiate into a T/NK cell that can become a T cell or an NK cell.

T/NK cells in the bone marrow respond to IL-15 and become NK cells.

T/NK cells in the thymus become T cells.



The Lymphoid System NK-cell activity is based on a balance of

inhibitory and activatory signals. NK cells are stimulated by exposure to

cytokines such as interleukin-12, interferon gamma, and interferon beta.

The inhibitory signal is based on recognition of MHC class I protein, expressed on all healthy self cells.



The Lymphoid System Diseased and cancerous cells tend to lose

their ability to produce MHC proteins. NK cells are thus triggered by a lack of MHC

antigens, sometimes referred to as recognition of “missing self" antigen

If an inhibitory signal is not received at the same time as the activatory signal, then NK cells release substances called perforins and granzymes. (See Figure 2-12 in text.)



The Lymphoid System NK cells can also recognize and lyse antibody-

coated cells through a process called antibody-dependent cell cytotoxicity.

Binding occurs through the CD16 receptor for IgG (Fc fragment).

Any target cell coated with IgG can be bound and destroyed.



The Lymphoid System Laboratory identification of T and B

lymphocytes utilizes flow cytometry. CD2, CD3, CD4,CD7, and CD8 are

recognized on T cells. CD19, CD20, CD21, CD22, and surface

immunoglobulin are recognized on B cells. CD 16,56 are found on NK cells

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